Measuring functional connectivity in frequency-domain helps to better characterize brain function.

Resting-state functional connectivity (FC) is widely used in multivariate pattern analysis of functional magnetic resonance imaging (fMRI), including identifying the locations of putative brain functional borders, predicting individual phenotypes, and diagnosing clinical mental diseases. However, limited attention has been paid to the analysis of functional interactions from a frequency perspective. In this study, by contrasting coherence-based and correlation-based FC with two machine learning tasks, we observed that measuring FC in the frequency domain helped to identify finer functional subregions and achieve better pattern discrimination capability relative to the temporal correlation. This study has proven the feasibility of coherence in the analysis of fMRI, and the results indicate that modeling functional interactions in the frequency domain may provide richer information than that in the time domain, which may provide a new perspective on the analysis of functional neuroimaging.

Parcellating the human brain using resting-state dynamic functional connectivity.

Brain cartography has expanded substantially over the past decade. In this regard, resting-state functional connectivity (FC) plays a key role in identifying the locations of putative functional borders. However, scant attention has been paid to the dynamic nature of functional interactions in the human brain. Indeed, FC is typically assumed to be stationary across time, which may obscure potential or subtle functional boundaries, particularly in regions with high flexibility and adaptability. In this study, we developed a dynamic FC (dFC)-based parcellation framework, established a new functional human brain atlas termed D-BFA (DFC-based Brain Functional Atlas), and verified its neurophysiological plausibility by stereo-EEG data. As the first dFC-based whole-brain atlas, the proposed D-BFA delineates finer functional boundaries that cannot be captured by static FC, and is further supported by good correspondence with cytoarchitectonic areas and task activation maps. Moreover, the D-BFA reveals the spatial distribution of dynamic variability across the brain and generates more homogenous parcels compared with most alternative parcellations. Our results demonstrate the superiority and practicability of dFC in brain parcellation, providing a new template to exploit brain topographic organization from a dynamic perspective. The D-BFA will be publicly available for download at https://github.com/sliderplm/D-BFA-618.

Aberrant temporal-spatial complexity of intrinsic fluctuations in major depression.

Accumulating evidence suggests that the brain is highly dynamic; thus, investigation of brain dynamics especially in brain connectivity would provide crucial information that stationary functional connectivity could miss. This study investigated temporal expressions of spatial modes within the default mode network (DMN), salience network (SN) and cognitive control network (CCN) using a reliable data-driven co-activation pattern (CAP) analysis in two independent data sets. We found enhanced CAP-to-CAP transitions of the SN in patients with MDD. Results suggested enhanced flexibility of this network in the patients. By contrast, we also found reduced spatial consistency and persistence of the DMN in the patients, indicating reduced variability and stability in individuals with MDD. In addition, the patients were characterized by prominent activation of mPFC. Moreover, further correlation analysis revealed that persistence and transitions of RCCN were associated with the severity of depression. Our findings suggest that functional connectivity in the patients may not be simply attenuated or potentiated, but just alternating faster or slower among more complex patterns. The aberrant temporal-spatial complexity of intrinsic fluctuations reflects functional diaschisis of resting-state networks as characteristic of patients with MDD.

Deep Transfer Learning for Cerebral Cortex Using Area-Preserving Geometry Mapping.

Limited sample size hinders the application of deep learning in brain image analysis, and transfer learning is a possible solution. However, most pretrained models are 2D based and cannot be applied directly to 3D brain images. In this study, we propose a novel framework to apply 2D pretrained models to 3D brain images by projecting surface-based cortical morphometry into planar images using computational geometry mapping. Firstly, 3D cortical meshes are reconstructed from magnetic resonance imaging (MRI) using FreeSurfer and projected into 2D planar meshes with topological preservation based on area-preserving geometry mapping. Then, 2D deep models pretrained on ImageNet are adopted and fine-tuned for cortical image classification on morphometric shape metrics. We apply the framework to sex classification on the Human Connectome Project dataset and autism spectrum disorder (ASD) classification on the Autism Brain Imaging Data Exchange dataset. Moreover, a 2-stage transfer learning strategy is suggested to boost the ASD classification performance by using the sex classification as an intermediate task. Our framework brings significant improvement in sex classification and ASD classification with transfer learning. In summary, the proposed framework builds a bridge between 3D cortical data and 2D models, making 2D pretrained models available for brain image analysis in cognitive and psychiatric neuroscience.

Altered cerebellar-motor loop in benign adult familial myoclonic epilepsy type 1: The structural basis of cortical tremor.

OBJECTIVE: Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar-motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME. METHODS: Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1-weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato-thalamo-(M1) (primary motor cortex) and globus pallidus internus (GPi)-thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted. RESULTS: Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato-thalamo-M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory-evoked potential P25-N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi-thalamic projection. Higher FA and lower RD in the right GPi-thalamic projection were also observed (FDR q < .05). SIGNIFICANCE: The present findings support the hypothesis that the cerebello-thalamo-M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.

Facial Kinship Verification: A Comprehensive Review and Outlook.

The goal of Facial Kinship Verification (FKV) is to automatically determine whether two individuals have a kin relationship or not from their given facial images or videos. It is an emerging and challenging problem that has attracted increasing attention due to its practical applications. Over the past decade, significant progress has been achieved in this new field. Handcrafted features and deep learning techniques have been widely studied in FKV. The goal of this paper is to conduct a comprehensive review of the problem of FKV. We cover different aspects of the research, including problem definition, challenges, applications, benchmark datasets, a taxonomy of existing methods, and state-of-the-art performance. In retrospect of what has been achieved so far, we identify gaps in current research and discuss potential future research directions.

Brain parcellation driven by dynamic functional connectivity better capture intrinsic network dynamics.

Until now, dynamic functional connectivity (dFC) based on functional magnetic resonance imaging is typically estimated on a set of predefined regions of interest (ROIs) derived from an anatomical or static functional atlas which follows an implicit assumption of functional homogeneity within ROIs underlying temporal fluctuation of functional coupling, potentially leading to biases or underestimation of brain network dynamics. Here, we presented a novel computational method based on dynamic functional connectivity degree (dFCD) to derive meaningful brain parcellations that can capture functional homogeneous regions in temporal variance of functional connectivity. Several spatially distributed but functionally meaningful areas that are well consistent with known intrinsic connectivity networks were identified through independent component analysis (ICA) of time-varying dFCD maps. Furthermore, a systematical comparison with commonly used brain atlases, including the Anatomical Automatic Labeling template, static ICA-driven parcellation and random parcellation, demonstrated that the ROI-definition strategy based on the proposed dFC-driven parcellation could better capture the interindividual variability in dFC and predict observed individual cognitive performance (e.g., fluid intelligence, cognitive flexibility, and sustained attention) based on chronnectome. Together, our findings shed new light on the functional organization of resting brains at the timescale of seconds and emphasized the significance of a dFC-driven and voxel-wise functional homogeneous parcellation for network dynamics analyses in neuroscience.

Dynamic neural circuit disruptions associated with antisocial behaviors.

Antisocial behavior (ASB) is believed to have neural substrates; however, the association between ASB and functional brain networks remains unclear. The temporal variability of the functional connectivity (or dynamic FC) derived from resting-state functional MRI has been suggested as a useful metric for studying abnormal behaviors including ASB. This is the first study using low-frequency fluctuations of the dynamic FC to unravel potential system-level neural correlates with ASB. Specifically, we individually associated the dynamic FC patterns with the ASB scores (measured by Antisocial Process Screening Device) of the male offenders (age: 23.29 ± 3.36 years) based on machine learning. Results showed that the dynamic FCs were associated with individual ASB scores. Moreover, we found that it was mainly the inter-network dynamic FCs that were negatively associated with the ASB severity. Three major high-order cognitive functional networks and the sensorimotor network were found to be more associated with ASB. We further found that impaired behavior in the ASB subjects was mainly associated with decreased FC dynamics in these networks, which may explain why ASB subjects usually have impaired executive control and emotional processing functions. Our study shows that temporal variation of the FC could be a promising tool for ASB assessment, treatment, and prevention.

Machine learning based on clinical characteristics and chest CT quantitative measurements for prediction of adverse clinical outcomes in hospitalized patients with COVID-19.

OBJECTIVES: To develop and validate a machine learning model for the prediction of adverse outcomes in hospitalized patients with COVID-19. METHODS: We included 424 patients with non-severe COVID-19 on admission from January 17, 2020, to February 17, 2020, in the primary cohort of this retrospective multicenter study. The extent of lung involvement was quantified on chest CT images by a deep learning-based framework. The composite endpoint was the occurrence of severe or critical COVID-19 or death during hospitalization. The optimal machine learning classifier and feature subset were selected for model construction. The performance was further tested in an external validation cohort consisting of 98 patients. RESULTS: There was no significant difference in the prevalence of adverse outcomes (8.7% vs. 8.2%, p = 0.858) between the primary and validation cohorts. The machine learning method extreme gradient boosting (XGBoost) and optimal feature subset including lactic dehydrogenase (LDH), presence of comorbidity, CT lesion ratio (lesion%), and hypersensitive cardiac troponin I (hs-cTnI) were selected for model construction. The XGBoost classifier based on the optimal feature subset performed well for the prediction of developing adverse outcomes in the primary and validation cohorts, with AUCs of 0.959 (95% confidence interval [CI]: 0.936-0.976) and 0.953 (95% CI: 0.891-0.986), respectively. Furthermore, the XGBoost classifier also showed clinical usefulness. CONCLUSIONS: We presented a machine learning model that could be effectively used as a predictor of adverse outcomes in hospitalized patients with COVID-19, opening up the possibility for patient stratification and treatment allocation. KEY POINTS: • Developing an individually prognostic model for COVID-19 has the potential to allow efficient allocation of medical resources. • We proposed a deep learning-based framework for accurate lung involvement quantification on chest CT images. • Machine learning based on clinical and CT variables can facilitate the prediction of adverse outcomes of COVID-19.

Functional Parcellation of Human Brain Precuneus Using Density-Based Clustering.

The human precuneus is involved in many high-level cognitive functions, which strongly suggests the existence of biologically meaningful subdivisions. However, the functional parcellation of the precuneus needs much to be investigated. In this study, we developed an eigen clustering (EIC) approach for the parcellation using precuneus-cortical functional connectivity from fMRI data of the Human Connectome Project. The EIC approach is robust to noise and can automatically determine the cluster number. It is consistently demonstrated that the human precuneus can be subdivided into six symmetrical and connected parcels. The anterior and posterior precuneus participate in sensorimotor and visual functions, respectively. The central precuneus with four subregions indicates a media role in the interaction of the default mode, dorsal attention, and frontoparietal control networks. The EIC-based functional parcellation is free of the spatial distance constraint and is more functionally coherent than parcellation using typical clustering algorithms. The precuneus subregions had high accordance with cortical morphology and revealed good functional segregation and integration characteristics in functional task-evoked activations. This study may shed new light on the human precuneus function at a delicate level and offer an alternative scheme for human brain parcellation.

Bayesian fusion and multimodal DCM for EEG and fMRI.

This paper asks whether integrating multimodal EEG and fMRI data offers a better characterisation of functional brain architectures than either modality alone. This evaluation rests upon a dynamic causal model that generates both EEG and fMRI data from the same neuronal dynamics. We introduce the use of Bayesian fusion to provide informative (empirical) neuronal priors - derived from dynamic causal modelling (DCM) of EEG data - for subsequent DCM of fMRI data. To illustrate this procedure, we generated synthetic EEG and fMRI timeseries for a mismatch negativity (or auditory oddball) paradigm, using biologically plausible model parameters (i.e., posterior expectations from a DCM of empirical, open access, EEG data). Using model inversion, we found that Bayesian fusion provided a substantial improvement in marginal likelihood or model evidence, indicating a more efficient estimation of model parameters, in relation to inverting fMRI data alone. We quantified the benefits of multimodal fusion with the information gain pertaining to neuronal and haemodynamic parameters - as measured by the Kullback-Leibler divergence between their prior and posterior densities. Remarkably, this analysis suggested that EEG data can improve estimates of haemodynamic parameters; thereby furnishing proof-of-principle that Bayesian fusion of EEG and fMRI is necessary to resolve conditional dependencies between neuronal and haemodynamic estimators. These results suggest that Bayesian fusion may offer a useful approach that exploits the complementary temporal (EEG) and spatial (fMRI) precision of different data modalities. We envisage the procedure could be applied to any multimodal dataset that can be explained by a DCM with a common neuronal parameterisation.

Enhanced Regional Functional Connectivity Indicates Seizure Onset Zone.

This project aims to explore if stronger functional connectivity (FC) exists in the maximal BOLD response of EEG/fMRI analysis when it is concordant with seizure-onset-zone (SOZ). Twenty-six patients with drug-resistant focal epilepsy who had an EEG/fMRI and later underwent stereo-EEG implantation were included. Different types of IEDs were labeled in scalp EEG and IED-related maximal BOLD responses were evaluated separately, each constituting one study. After evaluating concordance between maximal BOLD and SOZ, twenty-seven studies were placed in the concordant group and eight in the discordant group. We evaluated the local connectivity and ipsilaterally distant connectivity difference between the maximal BOLD and the contralateral homotopic region. Significantly stronger local FC was found for the maximal BOLD in the concordant group (p < 0.05, Bonferroni corrected). 52% of the studies in the concordant group and 13% in the discordant group had a significant difference compared to healthy subjects (p < 0.05, uncorrected). The finding suggests that, when concordant with the SOZ, the maximal BOLD is more likely to have stronger local FC compared to its contralateral counterpart. This asymmetry in functional connectivity may help to noninvasively improve the specificity of EEG/fMRI analysis.

Impact of global signal regression on characterizing dynamic functional connectivity and brain states.

Recently, resting-state functional magnetic resonance imaging (fMRI) studies have been extended to explore fluctuations in correlations over shorter timescales, referred to as dynamic functional connectivity (dFC). However, the impact of global signal regression (GSR) on dFC is not well established, despite the intensive investigations of the influence of GSR on static functional connectivity (sFC). This study aimed to examine the effect of GSR on the performance of the sliding-window correlation, a commonly used method for capturing functional connectivity (FC) dynamics based on resting-state fMRI and simultaneous electroencephalograph (EEG)-fMRI data. The results revealed that the impact of GSR on dFC was spatially heterogeneous, with some susceptible regions including the occipital cortex, sensorimotor area, precuneus, posterior insula and superior temporal gyrus, and that the impact was temporally modulated by the mean global signal (GS) magnitude across windows. Furthermore, GSR substantially changed the connectivity structures of the FC states responding to a high GS magnitude, as well as their temporal features, and even led to the emergence of new FC states. Conversely, those FC states marked by obvious anti-correlation structures associated with the default model network (DMN) were largely unaffected by GSR. Finally, we reported an association between the fluctuations in the windowed magnitude of GS and the time-varying EEG power within subjects, which implied changes in mental states underlying GS dynamics. Overall, this study suggested a potential neuropsychological basis, in addition to nuisance sources, for GS dynamics and highlighted the need for caution in applying GSR to sliding-window correlation analyses. At a minimum, the mental fluctuations of an individual subject, possibly related to ongoing vigilance, should be evaluated during the entire scan when the dynamics of FC is estimated.

Towards BCI-actuated smart wheelchair system.

BACKGROUND: Electroencephalogram-based brain-computer interfaces (BCIs) represent novel human machine interactive technology that allows people to communicate and interact with the external world without relying on their peripheral muscles and nervous system. Among BCI systems, brain-actuated wheelchairs are promising systems for the rehabilitation of severely motor disabled individuals who are unable to control a wheelchair by conventional interfaces. Previous related studies realized the easy use of brain-actuated wheelchairs that enable people to navigate the wheelchair through simple commands; however, these systems rely on offline calibration of the environment. Other systems do not rely on any prior knowledge; however, the control of the system is time consuming. In this paper, we have proposed an improved mobile platform structure equipped with an omnidirectional wheelchair, a lightweight robotic arm, a target recognition module and an auto-control module. Based on the you only look once (YOLO) algorithm, our system can, in real time, recognize and locate the targets in the environment, and the users confirm one target through a P300-based BCI. An expert system plans a proper solution for a specific target; for example, the planned solution for a door is opening the door and then passing through it, and the auto-control system then jointly controls the wheelchair and robotic arm to complete the operation. During the task execution, the target is also tracked by using an image tracking technique. Thus, we have formed an easy-to-use system that can provide accurate services to satisfy user requirements, and this system can accommodate different environments. RESULTS: To validate and evaluate our system, an experiment simulating the daily application was performed. The tasks included the user driving the system closer to a walking man and having a conversation with him; going to another room through a door; and picking up a bottle of water on the desk and drinking water. Three patients (cerebral infarction; spinal injury; and stroke) and four healthy subjects participated in the test and all completed the tasks. CONCLUSION: This article presents a brain-actuated smart wheelchair system. The system is intelligent in that it provides efficient and considerate services for users. To test the system, three patients and four healthy subjects were recruited to participate in a test. The results demonstrate that the system works smartly and efficiently; with this system, users only need to issue small commands to get considerate services. This system is of significance for accelerating the application of BCIs in the practical environment, especially for patients who will use a BCI for rehabilitation applications.

Making group inferences using sparse representation of resting-state functional mRI data with application to sleep deprivation.

Past studies on drawing group inferences for functional magnetic resonance imaging (fMRI) data usually assume that a brain region is involved in only one functional brain network. However, recent evidence has demonstrated that some brain regions might simultaneously participate in multiple functional networks. Here, we presented a novel approach for making group inferences using sparse representation of resting-state fMRI data and its application to the identification of changes in functional networks in the brains of 37 healthy young adult participants after 36 h of sleep deprivation (SD) in contrast to the rested wakefulness (RW) stage. Our analysis based on group-level sparse representation revealed that multiple functional networks involved in memory, emotion, attention, and vigilance processing were impaired by SD. Of particular interest, the thalamus was observed to contribute to multiple functional networks in which differentiated response patterns were exhibited. These results not only further elucidate the impact of SD on brain function but also demonstrate the ability of the proposed approach to provide new insights into the functional organization of the resting-state brain by permitting spatial overlap between networks and facilitating the description of the varied relationships of the overlapping regions with other regions of the brain in the context of different functional systems. Hum Brain Mapp 38:4671-4689, 2017. © 2017 Wiley Periodicals, Inc.

Differentiating Patients with Parkinson's Disease from Normal Controls Using Gray Matter in the Cerebellum.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders in the world. Previous studies have focused on the basal ganglia and cerebral cortices. To date, the cerebellum has not been systematically investigated in patients with PD. In the current study, 45 probable PD patients and 40 age- and gender-matched healthy controls underwent structural magnetic resonance imaging, and we used support vector machines combining with voxel-based morphometry to explore the cerebellar structural changes in the probable PD patients relative to healthy controls. The results revealed that the gray matter alterations were primarily located within the cerebellar Crus I, implying a possible important role of this region in PD. Furthermore, the gray matter alterations in the cerebellum could differentiate the probable PD patients from healthy controls with accuracies of more than 95 % (p < 0.001, permutation test) via cross-validation, suggesting the potential of analyzing the cerebellum in the clinical diagnosis of PD.

Neurobiological basis of head motion in brain imaging.

Individual differences in brain metrics, especially connectivity measured with functional MRI, can correlate with differences in motion during data collection. The assumption has been that motion causes artifactual differences in brain connectivity that must and can be corrected. Here we propose that differences in brain connectivity can also represent a neurobiological trait that predisposes to differences in motion. We support this possibility with an analysis of intra- versus intersubject differences in connectivity comparing high- to low-motion subgroups. Intersubject analysis identified a correlate of head motion consisting of reduced distant functional connectivity primarily in the default network in individuals with high head motion. Similar connectivity differences were not found in analysis of intrasubject data. Instead, this correlate of head motion was a stable property in individuals across time. These findings suggest that motion-associated differences in brain connectivity cannot fully be attributed to motion artifacts but rather also reflect individual variability in functional organization.

Changes in functional connectivity dynamics associated with vigilance network in taxi drivers.

An increasing number of neuroimaging studies have suggested that the fluctuations of low-frequency resting-state functional connectivity (FC) are not noise but are instead linked to the shift between distinct cognitive states. However, there is very limited knowledge about whether and how the fluctuations of FC at rest are influenced by long-term training and experience. Here, we investigated how the dynamics of resting-state FC are linked to driving behavior by comparing 20 licensed taxi drivers with 20 healthy non-drivers using a sliding window approach. We found that the driving experience could be effectively decoded with 90% (p<0.001) accuracy by the amplitude of low-frequency fluctuations in some specific connections, based on a multivariate pattern analysis technique. Interestingly, the majority of these connections fell within a set of distributed regions named "the vigilance network". Moreover, the decreased amplitude of the FC fluctuations within the vigilance network in the drivers was negatively correlated with the number of years that they had driven a taxi. Furthermore, temporally quasi-stable functional connectivity segmentation revealed significant differences between the drivers and non-drivers in the dwell time of specific vigilance-related transient brain states, although the brain's repertoire of functional states was preserved. Overall, these results suggested a significant link between the changes in the time-dependent aspects of resting-state FC within the vigilance network and long-term driving experiences. The results not only improve our understanding of how the brain supports driving behavior but also shed new light on the relationship between the dynamics of functional brain networks and individual behaviors.

Altered cerebellar-cerebral functional connectivity in benign adult familial myoclonic epilepsy.

OBJECTIVE: The pathogenesis of benign adult familial myoclonic epilepsy (BAFME) remains unknown, although cerebellar pathologic changes and brain hyperexcitability have been reported. We used resting-state functional magnetic resonance imaging (fMRI) to examine the functional connectivity between the cerebellum and cerebrum in a Chinese family with BAFME for the first time. METHODS: Eleven adults with BAFME and 15 matched healthy controls underwent resting-state blood oxygen level-dependent (BOLD) fMRI scanning. The cerebellar seeds, including the bilateral crus I, lobule VIII, lobule VIIb, and lobule IV&V, were defined a priori. Next, regional time courses were obtained for each individual by averaging the BOLD time series over all voxels in each seed region. Then, seed-based functional connectivity z-maps were produced by computing Pearson's correlation coefficients (converted to z-scores by Fisher transformation) between each seed signal and the time series from all other voxels within the entire brain. Finally, a second-level random-effect two-sample t-test was performed on the individual z-maps in a voxel-wise manner. RESULTS: Reduced functional connectivity of the right cerebellar crus I with the left middle frontal gyrus and right cerebellar lobule IX was observed in the default network of BAFME. Enhanced functional connectivity of the left cerebellar lobule VIII with the bilateral middle temporal gyri, right putamen, and left cerebellar crus I was found in the dorsal attention network of BAFME. Enhanced functional connectivity between the left cerebellar lobule VIIb and right frontal pole was found in the control network of BAFME. SIGNIFICANCE: Altered cerebellar-cerebral functional connectivity may contribute to the understanding of the nosogenesis of BAFME and explain the cognitive dysfunction in this Chinese family with BAFME.

Negative hemodynamic response in the cortex: evidence opposing neuronal deactivation revealed via optical imaging and electrophysiological recording.

Functional brain imaging techniques depend on the relationship between regional hemodynamic responses and neural activity. The positive hemodynamic response (PHR) has widely been discussed and has generally been associated with an increase in neuronal signals. In contrast, the negative hemodynamic response (NHR) has not been investigated extensively, and its underlying nature is highly controversial. In the present study, we employed an optical imaging (OI) technique and microelectrode array (MEA) recordings in the rat cortex to examine the NHR to hindlimb electrical stimulation; we primarily focused on the NHR adjacent to a PHR region. We determined that the dynamics of the total blood volume signal in the NHR regions lagged slightly behind those in the PHR areas. Additionally, the deoxyhemoglobin signal in the PHR areas increased immediately after stimulation and the deoxyhemoglobin signal in the NHR regions remained unchanged or increased. Consistent with the change in the deoxyhemoglobin signal, the MEA recordings demonstrated that neural activity in the PHR regions was elevated and that activity in the NHR areas was unchanged or increased during stimulation, implying that the NHR occurred in the absence of neural deactivation. These results suggest that the NHR may be explained by purely hemodynamic contributions, specifically "blood stealing" or increased neural activity, and indicate that caution should be exercised when interpreting the NHR as a decrease in neural activity, especially when the NHR is adjacent to a PHR.